Project Summary There is compelling preclinical, epidemiological and clinical evidence of greater vulnerability in females for cocaine effects, including reward magnitude and positive subjective effects, rate of development of cocaine use disorder (CUD), and relapse risk following cocaine abstinence. Preclinical studies have demonstrated opposing effects of estradiol (activating) and progesterone (dampening) on behavioral and neurological responses to cocaine. The glutamate (Glu) system plays a central role in cocaine use, contributing to development and maintenance of regular use, withdrawal, and reinstatement following abstinence. Importantly, recent brain imaging studies have shown significant reductions in mGluR5 binding potential (BPND) during cocaine abstinence. To date, however, CUD human brain imaging studies have enrolled only male subjects or have included too few female subjects to permit analyses as a function of sex. The proposed research will examine sex differences in mGluR5 BPND during cocaine withdrawal as a function of gonadal hormones in women and men with cocaine use disorder and in a comparison group of healthy controls. In response to reviewer concerns, this revised application adds fMRI scans to broaden examination of sex differences in neurocircuitry that is activated in parallel with the targeted glutamate system during cocaine withdrawal. fMRI procedures will include both resting state functional connectivity scans (rsFC) as well as cocaine cue-induced event-related scans (CC) to occur within-subject during cocaine abstinence. We are specifically adding cueing procedures because it is known that women are more sensitive to craving and other associated effects of cocaine cues, during the follicular phase of menses. We will enroll 20 female and 20 male non-treatment seeking CUD participants. On day 1, CUD subjects undergo cocaine infusion, complete positron emission tomography (PET) imaging using [18F]FPEB to quantify mGluR5 BPND, followed by rsFC and CC fMRI. Women will be in the luteal phase of their menstrual cycle. During the 15-day CRU stay, bloods will be collected for measurement of hormones, and subjects will complete measures of withdrawal severity, craving and mood. On day 15, subjects will undergo a second set of [18F]FPEB PET and fMRI scans. This proposal will be the first to: characterize mGluR5 in women and men with CUD; examine the relationship of mGluR5 to resting state and cocaine cued brain function and to key behavioral measures of cocaine withdrawal and craving. Most importantly, the potential role of sex hormones in these effects will be studied. Despite over three decades of research, there are no efficacious pharmacotherapies approved for cocaine treatment. Thus, there is a pressing need to identify new neurotransmitter targets for medication development and to address gender- specific treatment needs. Findings may inform personalized, sex specific interventions for cocaine treatment.